1. Field of the Invention
The present invention is directed to new carbapenem antibiotics in which the 2-substituent has the formula ##STR2## wherein n is 0, 1, 2, or 3, m is 1 or 2, o is 1 or 2, and R is C.sub.1 -C.sub.6 alkyl, allyl, propargyl, carboxymethyl, cyanomethyl or aralkyl where the aryl moiety is phenyl or heteroaryl and the alkyl moiety is C.sub.1 -C.sub.6 alkyl, said heterocyclic ring containing the sulfonium group being optionally substituted at a ring carbon atom or atoms by one or two C.sub.1 -C.sub.6 alkyl groups.
2. Description of the Prior Art
A number of .beta.-lactam derivatives containing the carbapenem nucleus ##STR3## have been disclosed in the literature. These carbapenem derivatives have been reported to possess utility as antibacterial agents and or .beta.-lactamase inhibitors.
The initial carbapenem compounds were natural products such as thienamycin of the formula ##STR4## obtained by fermentation of Streptomyces cattleya (U.S. Pat. No. 3,950,357). Thienamycin is an exceptionally potent broad-spectrum antibiotic which possesses notable activity against various Pseudomonas species, organisms which have been notoriously resistant to .beta.-lactam antibiotics.
Compounds of the formula ##STR5## wherein R.sup.5, R.sup.6 and R.sup.7 are independently selected from H and substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl are disclosed in U.S. Pat. No. 4,235,920. Among the compounds disclosed in U.S. Pat. No. 4,235,920 is ##STR6## wherein A is a pharmaceutical acceptable anion. The abovementioned quaternary amine derivative is also described in Recent Advances in Chemistry of .beta.-Lactam Antibiotics, Royal Society of Chemistry, London, 1981, pg 240-254, where its antibacterial activity on average is reported as approximately 1/2 to 2/3 that of thienamycin.
Compounds of the formula ##STR7## attached to the amino nitrogen group of thienamycin represents a mono- or polycyclic N-containing heterocyclic group and R is H, substituted or unsubstituted: alkyl, aryl, alkenyl, heterocyclyalkenyl, aralkenyl, heterocyclyalkyl, aralkyl, --NR.sub.2, COOR, CONR.sub.2, --OR, or CN, are disclosed in European patent application No. 21082.
European Patent Application No. 40,408 discloses compounds of the formula ##STR8## wherein R.sup.1 is H, methyl or hydroxyl and R.sub.51 is a monovalent organic group including inter alia heterocyclicalkyl.
European Patent Application No. 38,869 discloses compounds of the formula ##STR9## wherein R.sup.6, R.sup.7, and R.sup.8 are independently selected from the group consisting of hydrogen, substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: ##STR10## wherein, relative to the above listed substituents on R.sup.6, R.sup.7, and R.sup.8, the groups R.sup.1 and R.sup.2 are independently selected from: hydrogen, alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms. (See also European Patent Applications Nos. 1627, 1628, 10317, 17992, 37080, 37081 and 37082).
At the Gordon Research Conference on Medicinal Chemistry held at New London, N.H. on Aug. 2-6, 1982, a handout was distributed in which a variety of carbapenem antibiotics were disclosed. Among the compounds disclosed on page 9 of the handout is the carbapenem of the formula ##STR11##
The above-mentioned carbapenem derivative is also disclosed on page 145 of European Patent Applicaton No. 38869 and on page 252 of European Patent Application No. 17992.
U.S. Pat. No. 4,309,346 discloses carbapenum derivatives having 2-substituents of the formula EQU --SR.sup.8
where R.sup.8 may be inter alia heteroaralkyl in which the hetero atom or atoms in heteroaralkyl may be selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms. No disclosure is made of any sulfonium groups such as are present in the compounds of the present invention.
European Patent Application No. 10,317 (see also U.S. Pat. No. 4,232,036) discloses carbapenem compounds of the general formula ##STR12## where R.sup.o is H or --SR.sup.8 ; R.sup.1, R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of hydrogen (R.sup.1 is not H), substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the alkyl chain has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: amino, mono-, di-, and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms.
U.K. Patent Application No. 2,119,371A discloses carbapenem antibiotics characterized by a 2-substituent of the formula ##STR13## in which A represents cyclopentylene, cyclohexylene or C.sub.2 -C.sub.6 alkylene optionally substituted by one or more C.sub.1 -C.sub.4 alkyl groups and ##STR14## represents a quaternized nitrogen-containing aromatic heterocycle.
U.K. Patent Application No. 2,122,196A discloses carbapenem antibiotics characterized by a 2-substituent of the formula ##STR15## in which A represents cyclopentylene, cyclohexylene or C.sub.2 -C.sub.6 alkylene optionally substituted by one or more C.sub.1 -C.sub.4 alkyl groups; R.sup.5 represents either (a) an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic radical or (b) a divalent phenylene or C.sub.1 -C.sub.4 alkylene group joined to the ##STR16## ring so as to form a bridged polycyclic group; and ##STR17## represents a quaternized nitrogen-containing non-aromatic heterocycle.
U.K. Patent Application No. 2,128,187A discloses carbapenem antibiotics characterized by a 2-substituent of the formula ##STR18## in which A represents a C.sub.1 -C.sub.6 straight or branched chain alkylene group; R.sup.5 represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic radical and ##STR19## represents a nitrogen-containing aromatic heterocycle attached to the alkylene group A at a ring carbon atom and quaternized by substituent R.sup.5.
U.K. Patent Application No. 2,118,183A discloses carbapenem antibiotics characterized by a 2-substituent of the formula ##STR20## wherein A represents a C.sub.2 -C.sub.6 straight or branched chain alkylene group and R.sup.10 and R.sup.11 each independently represents optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaliphatic, or R.sup.10 and R.sup.11 taken together with the S.sym. to which they are attached represent an optionally substituted sulfur-containing heterocyclic ring. Example 1 of U.K. No. 2,118,183A discloses the carbapenem antibiotic of the formula ##STR21## which differs from the compounds of the present application in that the heterocyclic group of the 2-substituent is bonded to the ethylene group via the sulfonium group.
Although there are a vast number of carbapenem derivatives disclosed in the literature, there is still a need for new carbapenems since known derivatives may be improved upon in terms of spectrum of activity, potency, stability and/or toxic side effects.